Abiraterone (Zytiga®) for Prostate Cancer

Clinical Article

March 3, 2014

Prostate cancer accounts for approximately three out of every ten cancer diagnoses in Australian men. After lung cancer, it is the second most common cause of cancer death, due to its relatively high prevalence. However, compared to other cancers, it also has one of the highest survival rates; 92% at five years after diagnosis. The risk increases with age where approximately one in eight men are diagnosed with prostate cancer by the age of 85.

Androgens play a major role in promoting the growth of the prostate. Initially, most prostate cancers use testosterone (the main male androgen hormone) to enhance tumour growth. The first line treatment of prostate cancer is based on androgen deprivation therapy, which aims to reduce or obliterate testosterone levels.

As testosterone is primarily produced in the testes, therapies are directed at reducing testosterone production in this area. This can be achieved through treatment with luteinizing hormone releasing hormone (LHRH) analogues, which involves hormonal suppression of testosterone production through a negative feedback mechanism, or by orchidectomy (surgical removal of one or both testes).

Unfortunately, prostate cancer has the potential to grow despite lowering testosterone production in the testes. This is termed castrate resistant prostate cancer (CRPC). The enzyme cytochrome P (CYP) 17 is required for the production of testosterone and other androgens. This enzyme is primarily expressed in the testes, but is also found in the adrenal glands, and is relatively highly expressed in prostate tumour tissue. As a result, therapy which targets the testes alone may not be sufficient in treating prostate cancer.

Abiraterone is a new treatment option for CRPC, which acts by inhibiting CYP17, thus blocking the formation of androgens and decreasing testosterone levels. Unlike other testosterone lowering therapies, such as LHRH analogues, abiraterone blocks the production of testosterone in the adrenal glands and tumour, in addition to blocking production in the testes, due to the specific enzyme it targets. When abiraterone is given in combination with a LHRH analogue (or orchidectomy), testosterone levels have been found to be undetectable.

The evidence for the use of abiraterone is based on two randomised, double blind, placebo controlled, multicentre phase III clinical trials of patients with metastatic CRPC. All patients were using either a LHRH analogue or had previously had an orchidectomy. Patients were treated with abiraterone and prednisolone, or placebo and prednisolone.

In the first trial, the patients had all failed prior treatment with docetaxel. In this trial patients who received abiraterone had an increased overall survival rate compared to those who received placebo (median overall survival 15.8 months [95% CI 14.8-17.0] vs 11.2 months [10.4-13.1]; hazard ratio [HR] 0.74, 95% CI 0.64-0.86; p<0.0001).

In the second trial, patients had not received any prior chemotherapy. In this trial, patients who received abiraterone had a longer median time to initiation of cytotoxic chemotherapy (25.2 months vs 16.8 months; HR 0.58; 95% CI, 0.49 to 0.69; p < 0.001), among other secondary endpoints.

The overall survival for the abiraterone group was longer in this trial, but this was not statistically significant.

Abiraterone causes increased mineralocorticoid levels through inhibition of the CYP17 enzyme. This results in adverse effects such as peripheral oedema, hypokalaemia and hypertension. These effects are reduced by concurrent administration of a steroid (prednisolone), though they are still common. Prednisolone causes a reduction in the drive to produce mineralocorticoids, through suppression of the adrenocorticotropic hormone (ACTH).

The mineralocorticoid effects can exacerbate heart failure and arrhythmias (e.g. atrial fibrillation or tachycardia). Patients with uncontrolled hypertension, myocardial infarction, arterial thrombotic events (within six months prior to initiation of treatment), severe or unstable angina, New York Heart Association class III or IV heart disease, or cardiac ejection fraction measurement of < 50%, were all excluded from the clinical trial. Caution is recommended when using abiraterone in these subgroups.

Abiraterone should be taken on an empty stomach, at least two hours after, or one hour before, food. Food increases the absorption of abiraterone, however the safety of this has not been assessed. It is available in 250mg tablets; the usual recommended dose is 1g once daily, which can be reduced in response to toxicity.

Abiraterone is always given in combination with prednisolone, either 5mg twice a day or 10mg once a day (prednisolone should be taken with food). Abiraterone is cleared by the liver, hence it is not recommended in patients with moderate to severe liver disease.

Abiraterone is a CYP enzyme inhibitor, so it may reduce the metabolism of drugs affected by these enzymes. It is a strong inhibitor of the CYP2D6 and CYP1A2 enzyme-subgroups. Caution is advised when abiraterone is prescribed with drugs metabolised by, or activated by, CYP2D6; dose adjustments may be necessary.

One small in-vitro study found that when abiraterone was given with a single dose of dextromethorphan (which is metabolised primarily by CYP2D6), the concentration of dextromethorphan increased by 200%.

On the other hand, the same study showed the concentration of a single dose of theophylline (a CYP1A2 substrate) was not affected when given in combination with abiraterone (plus prednisolone). As abiraterone is a relatively new drug, patient monitoring is recommended to ensure any side effects or interactions can be effectively managed if they arise. Abiraterone is also a moderate inhibitor of CYP2C9, CYP2C19 and CYP3A4/5; the clinical significance of this is still unknown but thought to be minor.

Abiraterone has recently been listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of metastatic CRPC in patients who have failed treatment with docetaxel due to resistance or intolerance, and who have a World Health Organisation performance status of two or less.

As with many chemotherapy treatments, the treatment will no longer be subsidised if disease progression occurs while the patient is on abiraterone. To qualify for the subsidy, the treatment must be in combination with prednisone or prednisolone, and must not be used in combination with other chemotherapy.

Abiraterone has a unique mechanism of action which justifies its place in therapy as a third-line treatment. Previously only available privately at a high cost to the patient, it is a welcome addition to the PBS, providing another treatment option for patients with castration resistant prostate cancer.